IL-15/IL-15Rα Heterodimeric Complex as Cancer Immunotherapy in Murine Breast Cancer Models

Abstract

Interleukin 15 (IL-15) has been evaluated as a potential treatment for solid tumors in clinical trials, but the effectiveness of systemic IL-15 administration as a monotherapy has not been realized. IL-15 receptor alpha (IL-15Rα) can stabilize IL-15 and enhance its bioactivity. The goal of this study was to examine the activity of IL-15/IL-15Rα complex (IL-15cx) to CD8+ T cells and evaluate its potential efficacy in murine breast cancer models. The antitumor efficacy was studied in mouse mammary carcinoma models (Her2/neu transgenic and 4T1-luc mammary cancers) treated with systemic recombinant protein with/without the depletion of myeloid-derived suppressor cells or intra-tumoral gene electrotransfer (GET). IL-15cx shows superior in vivo bioactivity to expand CD8 T cells in comparison to an equimolar single chain IL-15. T-bet is partially involved in CD8 T cell expansion ex vivo and in vivo due to IL-15 or IL-15cx. Intraperitoneal administration of IL-15cx results in a moderate inhibition of breast cancer growth that is associated with an increase in the frequency of cytotoxic CD8 T cells and the improvement of their function. The depletion of myeloid-derived suppressor cells (MDSCs) has no impact on mouse breast cancer growth. IL-15cx treatment diminishes MDSCs in murine tumors. However, it also antagonizes the effects of anti-Gr-1 depleting antibodies. Intratumoral GET with plasmid IL-15/IL-15Rα leads to a long-term survival benefit in 4T1 mammary carcinoma model. An early increase of local cytotoxic cells correlates with GET treatment and an increase of long-term memory T cells results from animals with complete tumor regression. Systemic and local administration of IL-15cx shows two distinct therapeutic responses, a moderate tumor growth inhibition or heterogeneous tumor regressions with survival improvement. Further studies are warranted to improve the efficacy of IL-15cx as an immunotherapy for breast cancer.

Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer

“…IL-15Ra can undergo trans-endosomal recycling in a complex with its ligand (IL-15), allowing for the continual re-appearance of the cytokine at the cell surface (Dubois et al, 2002), prolonging activation of IL-15Ra + cells long after the original IL-15 stimulus is removed. These dynamics (Bessard et al, 2009;Desbois et al, 2016;Guo et al, 2020;Wrangle et al, 2018), but have not yet formally been evaluated in human PDA. Our findings suggest that trials assessing the efficacy of this approach are warranted; a notion further supported by our observation that NIZ985 efficacy is enhanced in combination with chemotherapy.…”

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

“…Olesch et al have shown that ablation of S1PR4 enhances CD8 + T cell proliferation and increases tumor control by the PIK3AP1 and LTA4H regulation [ 157 ]. Additionally, IL-15/IL-15Rα, a heterodimeric complex, increases the expansion of CD8 + T cells superior to equimolar single-chain IL-15 influencing the T-bet pathway [ 158 ]. p38 mitogen-activated protein kinase (p38), a regulator of T cell proliferation and differentiation, contributes to the invasive and metastatic phenotype of TNBC.…”

Monocytic Myeloid-Derived Suppressor Cells Inhibit Myofibroblastic Differentiation in Mesenchymal Stem Cells Through IL-15 Secretion

“…Previous studies have reported that IL-15 is associated with the induction of various immune cells. Guo et al (2020) found that IL-15/IL-15Ra complex treatment diminished MDSCs in murine breast tumors. We next investigated whether IL-15 participated in regulating MDSCs during renal fibrosis.…”